Development and validation of a scoring system to predict esophagogastroduodenoscopy necessity.

OBJECTIVE: This study aimed to develop and validate a scoring system for predicting the need for esophagogastroduodenoscopy (EGD) in clinical practice to enhance accuracy and reduce misapplications. METHODS: From February 2021 to April 2022, outpatients scheduled for EGD at the Department of Gastroenterology in our hospital were recruited. Patients completed the system evaluation by providing clinical symptoms, relevant medical history, and endoscopic findings. Patients were randomly divided into the training and validation cohorts (at 2:1 ratio). The optimal algorithm was selected from five alternatives including a parallel test. Six physicians participated in a human-computer comparative validation. Sensitivity and negative likelihood ratio (-LR) were used as the primary indicators. RESULTS: Altogether 865 patients were enrolled, with 578 in the training cohort and 287 in the validation cohort. The scoring system comprised 21 variables, including age, 13 typical clinical symptoms, and seven medical history variables. The parallel test was selected as the final algorithm. Positive EGD findings were reported in 54.5% of the training cohort and 62.7% of the validation cohort. The scoring system demonstrated a sensitivity of 79.0% in the training cohort and 83.9% in the validation cohort, with -LR being 0.627 and 0.615, respectively. Compared to physicians, the scoring system exhibited higher sensitivity (84.0% vs 68.7%, P = 0.02) and a lower -LR (1.11 vs 2.41, P = 0.439). CONCLUSIONS: We developed a scoring system to predict the necessity of EGD using a parallel test algorithm, which was user-friendly and effective, as evidenced by single-center validation.

Establishment of animal model of gastroesophageal reflux disease by per-oral endoscopic tunneling: a preliminary study.

BACKGROUND: Although a variety of antireflux procedures and medications are used to treat gastroesophageal reflux disease (GERD), reliable large-animal models of GERD that can be used to objectively compare the efficacy of these treatments are lacking. We developed a method to establish large animal models of GERD by endoscopic sphincterotomy to develop an endoscopic treatment for GERD. METHODS: In this study six flesh swine carcasses were used. A full thickness incision was made at the esophageal site 5 cm above the dentate line by per-oral endoscopic tunneling. Esophageal radiography was conducted before and after surgery to observe changes at the site of the lower esophagus 5 cm above the dentate line and in the cardia. RESULTS: There was no significant change in the diameter of the esophageal site 5 cm above the dentate line before and after surgery, while the cardiac orifice significantly relaxed after surgery and enabled the contrast agent to smoothly travel through. The difference in diameter was statistically significant (P<0.05). CONCLUSIONS: Our experiments showed that it is a minimally invasive and mature technology of establishing GERD animal models by using the per-oral endoscopic tunneling technique, and might be a new method to establishing GERD large animal models.

Peroral endoscopic cardial constriction in gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) is a major digestive health problem with a high and increasing incidence worldwide. Peroral endoscopic cardial constriction (PECC) was developed by our group to provide a less invasive treatment for GERD.In this preliminary follow-up study, 16 patients were enrolled and 13 patients with GERD were targeted for analysis according to the Los Angeles classification of reflux esophagitis. The GERD health-related quality of life (GERD-HRQL) scale and esophageal pH monitoring were applied to assess clinical efficiency at 3 and 6 months after PECC treatment, respectively.All GERD patients successively received PECC, and no severe treatment-related complication was reported. Before PECC treatment, the GERD-HRQL scale was 19.92 ±â€Š7.89. At 3 and 6 months after treatment, the GERD-HRQL scale was 4.46 ±â€Š4.31 and 5.69 ±â€Š5.07, respectively. DeMeester score was 125.50 ±â€Š89.64 before PECC treatment, and 16.97 ±â€Š12.76 and 20.32 ±â€Š15.22 at 3 and 6 months after PECC treatment. Furthermore, the fraction time of a pH below 4 significantly decreased at 3 and 6 months after PECC treatment. Fraction time at pH <4 was 35.55 ±â€Š26.20 before PECC treatment and 7.96 ±â€Š13.03 and 4.72 ±â€Š3.78 at 3 and 6 months after PECC treatment, respectively. These results suggest that PECC treatment could significantly reduce the GERD-HRQL scale and DeMeester score (P < .01).PECC is a feasible, safe, and effective method to treatment GERD through narrowing the diameter of the cardia and preventing the reflux of stomach contents.

Nuclear factor-kappaB mediates cytoprotection of hydrogen peroxide preconditioning against apoptosis induced by oxidative stress in PC12 cells.

1. Cytoprotection by H(2)O(2) preconditioning against oxidative stress-induced apoptosis of PC12 cells has been demonstrated previously. In the present study, we investigated the effects of H(2)O(2) preconditioning on nuclear factor (NF)-kappaB activation and the role of NF-kappaB in the adaptive cytoprotection of H(2)O(2) preconditioning in PC12 cells. 2. The PC12 cells were preconditioned with 100 micromol/L H(2)O(2) for 90 min, followed by 24 h recovery and subsequent exposure to 300 micromol/L H(2)O(2) for a further 12 h. 3. The results showed that preconditioning with 100 micromol/L H(2)O(2) upregulated NF-kappaB expression and enhanced its nuclear translocation and DNA binding activity. In addition to its own effects on NF-kappaB expression, H(2)O(2) preconditioning also promoted the overexpression of NF-kappaB induced by a lethal concentration of H(2)O(2) (300 micromol/L). 4. N-Tosyl-l-phenylalanine chloromethyl ketone (TPCK; 20 micromol/L), an inhibitor of NF-kappaB, was administered 20 min before preconditioning with 100 micromol/L H(2)O(2). At this concenteration, TPCK blocked the overexpression of NF-kappaB induced by H(2)O(2) preconditioning, accompanied by attenuation of H(2)O(2) preconditioning-induced cytoprotection. The inhibition of NF-kappaB by TPCK enhanced caspase 3 activity induced by 300 micromol/L H(2)O(2). 5. The findings of the present study provide novel evidence for the effects of preconditioning with H(2)O(2) on constitutive activation of NF-kappaB, which contributes to the adaptive cytoprotection of H(2)O(2) preconditioning against PC12 cells apoptosis.

Inhibition of neuronal nitric oxide synthase antagonizes morphine antinociceptive tolerance by decreasing activation of p38 MAPK in the spinal microglia.

We have demonstrated that the activation of p38 mitogen-activated protein kinase (MAPK) in the spinal microglia played an essential role in the development of morphine antinociceptive tolerance. The aim of this study was to investigate whether inhibition of neuronal nitric oxide synthase (nNOS) attenuated tolerance to morphine analgesia by modulating p38 activation in the spinal microglia. It was shown that the selective inhibitor of nNOS, 7-NINA (7-Nitroindazole, sodium salt) (25 microg, i.t.) attenuated not only the development of morphine antinociceptive tolerance, but also the activation of p38 MAPK in the spinal microglia induced by chronic intrathecal administration of morphine. Our results suggest that neuronal NO signals to microglia, leading to the upregulation of microglial phospho-p38 MAPK. Such p38 MAPK activation in microglia is consistent with a potential role in the development of morphine antinociceptive tolerance. We demonstrated for the first time that the inhibition of nNOS attenuated morphine antinociceptive tolerance by reducing p38 MAPK activation in the spinal microglia.

Inducible nitric oxide synthase and cyclooxgenase-2 mediate protection of hydrogen peroxide preconditioning against apoptosis induced by oxidative stress in PC12 cells.

The induction of inducible nitric oxide synthase (iNOS) in response to different stress is associated with simultaneous induction of cyclooxygenase-2 (COX-2) in various cell types. Both iNOS and COX-2 have been reported to mediate the late phase of cardioprotection induced by different preconditioning. However, whether both iNOS and COX-2 are mediators in the neuroprotection induced by preconditioning with hydrogen peroxide (H(2)O(2)) at low concentration is unknown. In this study, using the neurosecretory cell line-PC12 cells to set up the model of neuroprotection of preconditioning with H(2)O(2) against apoptosis, we first investigate what changes in expression of iNOS and COX-2 appear during H(2)O(2) preconditioning, then determine if both iNOS inhibitor and COX-2 inhibitor interfere with the neuroprotection elicited by preconditioning with H(2)O(2). We found that preconditioning with H(2)O(2) at 10 microM significantly protected PC12 cells against apoptosis induced by lethal H(2)O(2) (50 microM) and increased the expression of iNOS and COX-2 and that selective iNOS inhibitor, aminoguanidine (AG) and COX-2 inhibitor, NS-398 obviously blocked the protective effects induced by preconditioning with 10 microM H(2)O(2). The results of this study suggest that both iNOS and COX-2 are mediators of the neuroprotection induced by preconditioning with oxidative stress (H(2)O(2) at low concentration) in PC12 cells.

Activation of p38 mitogen-activated protein kinase in spinal microglia mediates morphine antinociceptive tolerance.

Compelling evidence has suggested that spinal glial cells were activated by chronic morphine treatment and involved in the development of morphine tolerance. However, the mechanisms of glial activation were still largely unknown in morphine tolerance. In present study, we investigated the role of p38 mitogen-activated protein kinase (p38 MAPK) in the spinal cord in the development of chronic morphine antinociceptive tolerance. We found that intrathecal administration of morphine (15 microg) daily for 7 consecutive days significantly induced an increase in number of phospho-p38 (p-p38) immunoreactive cells in the spinal cord compared with chronic saline or acute morphine treated rats. Double immunofluorescence staining revealed that p-p38 immunoreactivity was exclusively restricted in the activated spinal microglia, not in astrocytes or neurons. Repeated intrathecal administration of 4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)-1H-imidazole (SB203580) (10 microg or 2 microg), a specific p38 inhibitor, 30 min before each morphine injection for 7 consecutive days significantly attenuated tolerance to morphine analgesia assessed by tail flick test. However, a single intrathecal administration of SB203580 (10 microg) did not antagonize the established tolerance to morphine analgesia. Taken together, these findings suggested that p38 MAPK activation in the spinal microglia was involved in the development of morphine antinociceptive tolerance. Inhibition of p38 MAPK by SB203580 in the spinal cord attenuated but not reversed the tolerance to morphine analgesia. The present study provides the first evidence that p38 activation in spinal microglia played an important role in the development of tolerance to morphine analgesia.

Protection of oxidative preconditioning against apoptosis induced by H2O2 in PC12 cells: mechanisms via MMP, ROS, and Bcl-2.

The present study is designed to investigate the effects of preconditioning with different doses of hydrogen peroxide (H2O2) on oxidative stress-induced apoptosis and the changes in mitochondrial membrane potential (MMP), intracellular reactive oxygen species (ROS) level, and expression of Bcl-2 during H2O2 preconditioning in rat pheochromocytoma (PC12) cells. It was shown that (1) H2O2 induced apoptosis in PC12 cells in a dose-dependent manner; (2) the preconditioning with 10 micromol L(-1) or 20 micromol L(-1) H2O2 can significantly protect PC12 cells against apoptosis induced by 50 or 100 micromol L(-1) H2O2, low (5 micromol L(-1)) and higher (30 micromol L(-1)) concentrations of H2O2 had no cytoprotections; (3) high concentration (100 micromol L(-1)) of H2O2 reduced MMP and expression of Bcl-2, and increased ROS level, but these effects were blocked by preconditioning with 10 micromol L(-1) H2O2; (4) the preconditioning with 10 micromol L(-1) H2O2 induced overexpression of Bcl-2. These results suggested that the preconditioning with low dose of H2O2 could protect the oxidative stress-induced PC12 cells apoptosis not only by preventing the reduction of MMP and expression of Bcl-2 as well as increase in ROS level, but also through overexpression of Bcl-2. It was indicated that overexpression of Bcl-2 may play a key role in the cytoprotection induced by preconditioning with low dose of H2O2 in PC12 cells.